In regenerative medicine, cell-based therapies (CBTs) comprise all medical treatments in which cells are the central component. Yet a cell-based therapy is not one single type of treatment: approaches differ in the donor, the tissue the cells originate from, how they are separated and prepared, their exhibited characteristics, and the site of delivery. RegMed Austria supports internationally recognized standards for describing and reporting these therapies precisely, such as the DOSES consensus tool, so that different approaches are not treated as if they were interchangeable.
Only in part. The International Society for Cell & Gene Therapy recommends the term mesenchymal stromal cells, because MSC preparations are heterogeneous and only a small subpopulation shows true self-renewal and multilineage differentiation in vivo. Current evidence suggests that most therapeutic effects are mediated by paracrine and immunomodulatory signalling rather than by engraftment and differentiation of the administered cells. Precise terminology, such as that provided by the DOSES tool, is therefore essential.
iPSCs are somatic cells reprogrammed into a pluripotent state by defined transcription factors (Yamanaka, 2006/2007). Like embryonic stem cells, they can give rise to virtually any cell type, but they avoid the ethical issues associated with the use of embryos. Their clinical application is still experimental and limited to controlled trials, for example with retinal pigment epithelium or dopaminergic neurons. Key concerns are teratoma formation from residual undifferentiated cells and genetic or epigenetic aberrations acquired during reprogramming and culture. iPSC-derived products are laboratory-manufactured advanced therapies and therefore fundamentally different from, for example, autologous point-of-care preparations.
Multilineage-differentiating stress-enduring (Muse) cells are a subpopulation of MSCs, identified by co-expression of SSEA-3 and CD105. They are found in bone marrow, adipose tissue, peripheral blood and connective tissue. Muse cells show pluripotent-like differentiation capacity and tolerance to cellular stress, and they home to damaged tissue. Unlike embryonic stem cells and iPSCs, they do not form teratomas. |
Exosomes are a subtype of extracellular vesicles (EVs), roughly 30–150 nm in size, which carry proteins, lipids and RNA and mediate part of the paracrine effect of cells. As a “cell-free” approach they are of great scientific interest. However, isolation, characterization and dosing are not yet standardized (see the Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines of the International Society for Extracellular Vesicles), and clinical data remain limited. Therapeutic EV products are medicinal products that require regulatory approval. Products marketed outside clinical trials should be viewed critically. But EV from autologous procedures are fine.
Adult stem and progenitor cells have limited proliferative capacity and are physiologically present in every individual. The documented cases of cell-therapy-associated tumours involved fetal or allogeneic cells, often culture-expanded and administered in unregulated settings. Theoretical risks apply mainly to pluripotent cells (teratoma formation), extensive culture expansion (genetic instability) and the potential of MSCs to support pre-existing malignancies through stromal and immunomodulatory effects; active malignancy is therefore generally regarded as a contraindication. For autologous, minimally manipulated adult cell preparations, there is no evidence of de novo tumour formation, and based on current data the risk is considered very low.
No. PRP is an autologous blood product in which platelets, which are cell fragments without a nucleus, are concentrated and release growth factors. It contains no or only few nucleated cells, depending on the system used. PRP is therefore classified as an orthobiologic, not as a cell-based therapy. It is often combined with cell preparations such as bone marrow aspirate concentrate (BMAC), which should be clearly reported.
Probably yes, but optimal doses have not been established for most indications. Several studies suggest a relationship between progenitor cell dose, e.g. CD34+ cells or colony-forming units (CFU-F), and clinical outcome. Cell yield varies considerably between individuals. An age-related decline is frequently reported, but not consistently: in a cohort of 729 children and adults, Pabinger et al. (2021) observed a plateau rather than a continuous decrease. Moreover, cell counts depend on the aspiration technique and on the analytical method (e.g. flow cytometry gating strategy), which limits comparability between studies. Cell number and viability should therefore be quantified with standardized methods and documented for every preparation; only then can dose–response relationships be studied reliably.
Regulation depends mainly on the degree of manipulation and on whether the cells serve the same essential function at the site of application (homologous use). Substantially manipulated cells, such as culture-expanded cells, and cells used non-homologously are generally classified as advanced therapy medicinal products (ATMPs) under Regulation (EC) No 1394/2007. Autologous cells used within the same surgical procedure are subject to specific exemptions. Classification is often case-specific; details are addressed in a separate topic.
It varies considerably by indication and type of procedure. At the top of the evidence hierarchy are evidence-based clinical guidelines, which build on systematic reviews and formally grade the certainty of evidence and strength of recommendations. They are followed by systematic reviews and meta-analyses of randomized controlled trials (RCTs), individual RCTs, cohort and case-control studies, and case series. Expert consensus statements rank lowest in terms of efficacy evidence, but play an important role in standardizing terminology and reporting – the DOSES tool is one example.
RCTs face a particular challenge in cell-based therapies: a placebo-controlled design requires sham procedures, such as a sham bone marrow aspiration or sham injection. These expose control patients to procedural risks without potential benefit, which is ethically questionable, especially in children and in severe, progressive diseases, and is often not feasible in routine clinical practice. At the same time, placebo effects can be substantial, particularly in musculoskeletal and pain indications. Alternative designs, such as active comparators, delayed-treatment or crossover designs, and well-conducted prospective cohort and registry studies, are therefore of particular importance.
Haematopoietic stem cell transplantation (HSCT) for haematological malignancies is established standard therapy. For non-malignant indications, the full spectrum of evidence exists: guidelines, systematic reviews and meta-analyses, RCTs (e.g. in knee osteoarthritis), a large number of prospective and retrospective cohort studies, as well as case series and individual treatment attempts. Heterogeneous preparations and incomplete reporting, however, still make comparisons between studies difficult.
Autologous blood therapy (German: Eigenbluttherapie) is an umbrella term for heterogeneous procedures in which the patient’s own blood is re-administered. Classic autohaemotherapy – the intramuscular re-injection of small volumes of untreated or modified venous blood (e.g. ozonated or UV-irradiated) – originates from complementary medicine and has little supporting evidence. Modern processed blood products, such as PRP or autologous conditioned serum (ACS) enriched with anti-inflammatory cytokines like the interleukin-1 receptor antagonist, are standardized preparations with a growing body of clinical data, e.g. in osteoarthritis and radicular pain. None of these procedures is a cell-based therapy in the strict sense, and they should be clearly distinguished from it.